text: Since PAMAM dendrimers have shown penetration capability to a wide range of cell lines, simple PAMAM-drug complexes would affect a broad spectrum of cells upon introduction to a living system. Thus, additional targeting ligands are required for the selective penetration of cell types. For example, PAMAM derivatized with folic acid is preferentially taken up by cancer cells, which are known to overexpress the folate receptor on their surfaces. Attaching additional treatment methods along with the folic acid, such as boron isotopes, cisplatin, and methotrexate have proven quite effective. In the future, as synthetic control over dendrimer surface chemistry becomes more robust, PAMAM and other dendrimer families may rise to prominence alongside other major approaches to targeted cancer therapy.
  In a study of folic acid functionalized PAMAM, methotrexate was combined either as an inclusion complex within the dendrimer or as a covalent surface attachment. In the case of the inclusion complex, the drug was released from the dendrimer interior almost immediately when subjected to biological conditions and acted similarly to the free drug. The surface attachment approach yielded stable, soluble complexes which were able to selectively target cancer cells and did not prematurely release their cargo. Drug release in the case of the inclusion complex could be explained by the protonation of surface and interior amines under biological conditions, leading to unpacking of the dendrimer conformation and consequent release of the inner cargo. A similar phenomenon was observed with complexes of PAMAM and cisplatin.
  PAMAM dendrimers have also demonstrated intrinsic drug properties. One quite notable example is the ability for PAMAM dendrimers to remove prion protein aggregates, the deadly protein aggregates responsible for bovine spongiform encephalopathy ("mad cow disease") and Creutzfeldt–Jakob disease in humans. The solubilization of prions is attributed to the polycationic and dendrimeric nature of the PAMAMs, with higher generation (>G3) dendrimers being the most efficient; hydroxy-terminated PAMAMs as well as linear polymers showed little to no effect. Since there are no other known compounds capable of dissolving prions which have already aggregated, PAMAM dendrimers have offered a bit of reprieve in the study of such fatal diseases, and may offer additional insight into the mechanism of prion formation.